Lipophilic compounds restore wt function of neurodevelopmental-associated KCNQ3 mutations.

A major driver of neuronal hyperexcitability is dysfunction of K+ channels, including voltage-gated KCNQ2/3 channels. Their slow activation and deactivation kinetics produces a current that regulates membrane potential and impedes repetitive firing. Mutations in KCNQ2 and KCNQ3 lead to a wide spectrum of neurodevelopmental disorders (NDDs), ranging from benign familial neonatal seizures to severe epileptic encephalopathies and autism spectrum disorders. However, the impact of these mutations on KCNQ channel function remains poorly understood and existing treatments have unpleasant side effects. Here we use voltage clamp fluorometry and molecular dynamic simulations to investigate how R227Q and R236C, two novel NDD-causing mutations in the voltage sensor of KCNQ3, impair channel function. We show that the two mutations perturb channel gating by two distinct mechanisms: R227Q altering voltage sensor movement and R236C altering voltage sensor-to-gate coupling. Our study further shows that polyunsaturated fatty acids (PUFAs), a novel class of ion channel modulators, primarily target the voltage sensor domain in its activated conformation and yield partial and complete restoration of wt function in R227Q- and R236C-containing channels, respectively. Our results reveal the potential of PUFAs to be developed into therapies for diverse KCNQ3-based channelopathies.